Breast cancer cells respond to both steroid hormones such as estrogen and polypeptides growth factors such as insulin-like growth factor-1 (IGF-I) . Because increased IGF-I activity correlates with tumor cell aggressiveness in vitro, and may correlate with tumor responsiveness in breast cancer patients, we have investigated whether signal transduction pathways downstream from the IGF-I receptor are activated in breast cancer cells. Activation of Akt, MAPK, and isoforms of protein kinase C was noted in multiple breast cancer cell lines. Activation of the PI3K/Akt pathway was exploited using pharmacologic inhibitors and genetic approaches to inhibit Akt, which resulted in increased programmed cell death (apoptosis). Combining inhibition of the PI3K/Akt pathway with traditional forms of therapy such as chemotherapy, trastuzumab, and tamoxifen, increased therapeutic effectiveness. Increased therapeutic efficacy was associated with an induction of Akt activity by the agents themselves, suggesting that Akt activation by therapeutic agents may represent a new mechanism of therapeutic resistance. Exploitation of IGF-I stimulated signalling is a novel approach to promote breast cancer cell apoptosis and may eventually have therapeutic implications.